Stabilizer for radioactive colloidal solutions

ABSTRACT

A stabilizer for radioactive colloidal solutions prepared from three gelatin fractions of varying molecular weights. It is prepared by heating the fractions with water, sodium chloride and succinic anhydride followed by neutralization and bacterial filtration.

United States Patent Mikheev et al. [45] Mar. 27, 1973 1 STABILIZER FORRADIOACTIVE [56] References Cited COLLOIDAL SOLUTIONS UNITED STATESPATENTS [75] Inventors: Nikolai Borisovich Mikheev; Maia ArkadievnaGracheva, both of 3,127,313 3/1964 Glenn ..424/l X Moscow; LjubovGrigorievna OTHER PUBLICATIONS Bogomolova, Leningrad; Valentin IlichLevin, Moscow, all of U S R Bellion et a1, Nuclear Science Abstracts,Vol. 21, No.

14, July 31, 1967 item 24345, pp. 2571-2572. [73] Assignee: InstitutBiofiziki, Moscow, USSR.

g 8 ExaminerBenja.min R. Padgett Att0rney-Waters, Roditi, Schwartz &Nissen [21] Appl. No.: 848,714

' [57] ABSTRACT [52] U.S. Cl ..424/ 1, 252/30l.1 R, 252/301.1 S, Astabilizer for radioactive colloidal solutions 424/360 prepared fromthree gelatin fractions of varying [51] Int. Cl. ..A61k 27/04 molecularweights. It is preparedby heating the frac- [58] Field of Search ..260/117, 118; 424/1, 359, 360; tions with water, sodium chloride ands'uccinic anhydride followed by neutralization and bacterial filtration.

7 Claims, No Drawings STABILIZER FOR RADIOACTIVE COLL'OIDAL SOLUTIONSThe present invention relates to stabilizers of disperse systems and,more particularly, to stabilizers of colloidal solutions employed inmedicine and also in the oil producing and metal-working industries.

It is known to use gelatin as a stabilizer for colloidal solutions.

A disadvantage of employing gelatin as a stabilizer for colloidalsolutions used in medicine is that gelatin causes a pyrogenic reactionwhen introduced into the body parenterally. A disadvantage of employinggelatin as a stabilizer for radioactive colloidal solutions is thatgelatin is decomposed by radioactive radiation, thus leading tocoagulation of said colloidal solutions.

It is the primary object of the present invention to provide a newstabilizer insuring the stability of radioactive colloidal solutions.

Another object is to provide a stabilizer of colloidal solutions whichis suitable for introduction into the body and which withstands heatsterilization.

Other objects and features of advantage of the invention will beexplained in the ensuing description.

In accordance with the foregoing and other objects the inventionconsists essentially in the provision of a stabilizer for colloidalsolutions which, according to the invention, is modified gelatincomprising fractions having the following molecular weights: 20,00023-27 wt. percent; 10,000 45-55 wt. percent; and less than l0,000 theremainder. The gelatin may be, for example, skin or bone gelatin as setforth in U.S. Pat. No. 3,127,313 ofMar.3l,1964.

Said modified gelatin is prepared by the action of water, at a gaugepressure of l.l1.3 atm and a temperature of l25-l 35C, on a mixtureconsisting of gelatin, sodium chloride and succinic anhydride, followedby neutralization of the solution obtained and bacterial filtration ofthe same. We have tentatively named such modified gelatine gelatinol."

A stabilizer freed of calcium and magnesium ions is preferably employed.

The present stabilizer can be used for colloidal solutions prepared bythe condensation method and the reduction method.

The present stabilizer can be used in combination with otherstabilizers, preferably with saccharides.

In addition, the present stabilizer is used for preparing medical andradioactive colloidal solutions.

The method of preparing a colloidal solution by condensation comprisesadding gelatinol to the solutions of salts to be reacted to form thecolloidal solution, after which said solutions of salts are mixed.

The method of preparing a colloidal solution by reduction of the salt ofa noble metal comprises adding gelatinol to a solution of said saltafter which said salt is reduced.

It will be understood that the methods of preparing colloidal solutionsdescribed above are only two of the many possible variations of the useof gelatinol as a stabilizer of colloidal solutions. Gelatinol can alsobe used alone or in combination with other stabilizers for thepreparation of colloidal systems by other methods, for example, by thedispersion method, wherein the precipitate to be converted into thecolloidal state is dispersed in the presence of gelatinol. Inasmuch asgelatinol withstands a radiation load of not less than 1.5

millions rads, colloidal solutions stabilized with gelatinol are stableto radiation while in storage. In addition, gelatinol withstandssterilization by autoclaving, and therefore colloidal solutionsstabilized ,with gelatinol can be subjected to heat sterilization.Besides, colloidal solutions stabilized with gelatinol are suitable formedical use by injection. In some cases the use of gelatinol incombination with other stabilizers makes it possible to' increase thestability of colloidal solutions.

The present invention is illustrated in the following examples.

EXAMPLE 1.

Preparation of colloidal solution of chromium phosphate with P by thecondensation method.

3 ml of a solution of chrome alum having a chromium content of 6.75 gper liter is mixed with 30 ml of gelatinol which has been freed ofcalcium and magnesium ions and which contains fractions having thefollowing molecular weights: 20,000 24 wt. percent; 10,000 45 wt.percent; less than 10,000 31 wt. percent; said gelatinol being dilutedwith water in the proportion of l:7. The solution is heated to boilingand to it is added 14 ml of a solution of sodium hydrophosphate,radioactive from P and containing 6 mg of phosphorus, and 1.8 ml of theabove gelatinol but not diluted with water. The pH of the mixture isadjusted to 8.5 by the addition of sodium hydroxide. The colloidalsolution is passed through an ion-exchange column charged with an anionexchanger, for example, Dowex 2, to remove sulfate ion and unreactedphosphate ion. The product solution is packaged and subjected tofractional sterilization. The preparation contains not more than 2percent phosphorus in the ionized state and is stable in storage notless than 1 month.

EXAMPLE 2.

Preparation of colloidal solution of zirconyl phosphate with P by thecondensation method.

To 5 ml of a solution of zirconyl chloride containing ml of zirconiumper ml is added l0 ml of l N hydrochloric acid and 2 ml of a solution ofyttrium chloride containing 10 mg of yttrium per ml and the volume madeup to 100 ml with a solution of gelatinol which has been freed ofcalcium and magnesium ions and which contains fractions having thefollowing molecular weights: 20,000 27 wt. percent; [0,000 55 wt.percent; less than 10,000 18 wt percent; said gelatinol being dilutedwith distilled water in the proportion of 1:6. A solution of radioactivesodium hydrophosphate with the above gelatinol but not diluted withwater is prepared separately. To 10 ml of sodium hydrophosphatecontaining 5 mg of phosphorus per ml is added a solution of radioactivesodium hydrophosphate containing P and also 12 ml of gelatinol and thevolume is made up to 70 ml with water. The pH of the solution isadjusted to 2.2 with sterilized. The ionized phosphorus content in thepreparation does not exceed 1 percent of the total phosphorus content.The preparation is stable in storage for not less than 1 month. Beforemaking injections the acid colloidal zirconyl phosphate is neutralized.

EXAMPLE 3.

Preparation of colloidal solution of palladium containing Pd by thereduction method.

In an Erlenmeyer flask are placed 2 ml of 10 percent ascorbic acid, 2 mlof 0.5 N sodium hydroxide, 9 ml of twice-distilled water and 0.5 ml ofgelatinol of the composition specified in Example 1. The contents of theflask are heated on the water bath for 3 min and to the mixture is added0.5 ml of inactive palladium in 0.075 N hydrochloric acid containing 0.5mg of palladium per ml. The mixture is heated on the water bath for 5minutes, after which there is added 1.5 ml of the above gelatinol andheating continued for another 5 minutes. To the hot seeding" solutionthus prepared there is added dropwise with stirring 9.5 ml ofa palladiumsolution having a concentration of 0.5 mg Pd/ml in 0.075 N hydrochloricacid and containing Pd'. The flask is then heated on the water bath forminutes and neutralized with 0.5 N sodium hydroxide to pH 5. The productsolution is sterilized in the autoclave at a gauge pressure of 1 atm forminutes.

EXAMPLE 4.

Preparation of a colloidal solution of tin hydroxide tagged withtechnetium, using a combined stabilizer.

To 2 ml of isotonic sodium chloride solution containing To in the formof pertechnetate is added 0.15 ml of 1.2 percent stannic chloridesolution in a mixture of ethyl alcohol and 5 N hydrochloric acid in theproportion of 2:1 by volume. To the solution obtained is added 1 ml ofgelatinol containing fractions with the following molecular weights:20,000 wt. percent; 10,000 50 wt. percent; less than 10,000 25 wt.percent; and 1 ml of 40 percent glucose solution as a stabilizer. Themixture is stirred and allowed to stand for minutes. The solution isthen neutralized to pH 4.5 by the addition of 0.1 ml of a solutioncontaining 4 g of sodium hydroxide and 25 g of sodium acetate in 100 ml.

To prepare the colloidal solution in a sterile form the finishedpreparation can be sterilized by bacterial filtration. A colloidalsolution of tin containing T0 is suitable for diagnosing diseases of theliver and bone mar- TOW.

To prepare gelatinol a mixture consisting of 8 wt. percent of gelatin,0.9 wt. percent of sodium chloride, 0.2 wt.% of succinic anhydride and90.9 wt. percent of water is heated in an autoclave at a gauge pressureof 1.2 atm for 30 minutes. After cooling, autoclaving is repeated in thesame conditions. The preparation is then neutralized to pH 6.8-7 withsodium bicarbonate and sterilized by bacterial filtration.

in the above examples of the preparation of colloidal solutions thegelatinol used contained fractions with the following molecular weights:

1. 20,000 24 wt. percent; 10,000 45 wt. percent; less than 10,000 31 wt.percent;

2. 20,000 27 wt. percent; 10,000 55 wt. percent;

less than 10,000 18 wt, percent;

3. 20,000 25 wt. percent; 10,000 50 wt. percent;

less than 10,000 25 wt. percent.

The properties of the colloidal solutions obtained in Examples 1 through4 do not depend on the fractional content of the gelatinol.

We claim:

1. A method of making a stabilizer for colloidal solutions comprisingmixing gelatin containing fractions with the following molecularweights: 20,000 2327 wt. percent; 10,000 45-55 wt. percent, and lessthan 10,000 the remainder with water, at a gauge pressure of about l.ll.3 atm and a temperature of about l25l 3 5C, and with sodium chlorideand succinic anhydride, followed by neutralization of the solution thusobtained and by a bacterial filtration of said solution.

2. A method of making a stabilizer as claimed in claim 1 comprisingfreeing the solution of calcium and magnesium ions.

3. A method of making a stabilizer as claimed in claim 1 comprisingcombining the thusly obtained stabilizer with other stabilizers.

4. A method of making a stabilizer as claimed in claim 1, comprisingcombining the thusly obtained stabilizer with saccharides.

5. The stabilizer prepared according to the method claimed in claim 1.

6. The stabilizer claimed in claim 5 combined with a colloidal solutionprepared by the condensation or reduction methods.

7. The stabilizer claimed in claim 5 combined with medical orradioactive colloidal solutions.

2. A method of making a stabilizer as claimed in claim 1 comprisingfreeing the solution of calcium and magnesium ions.
 3. A method ofmaking a stabilizer as claimed in claim 1 comprising combining thethusly obtained stabilizer with other stabilizers.
 4. A method of makinga stabilizer as claimed in claim 1, comprising combining the thuslyobtained stabilizer with saccharides.
 5. The stabilizer preparedaccording to the method claimed in claim
 1. 6. The stabilizer claimed inclaim 5 combined with a colloidal solution prepared by the condensationor reduction methods.
 7. The stabilizer claimed in claim 5 combined withmedical or radioactive colloidal solutions.